Synaptotagmin I is a molecular target for lead

J Neurochem. 2001 Mar;76(6):1724-35. doi: 10.1046/j.1471-4159.2001.00168.x.


Lead poisoning can cause a wide range of symptoms with particularly severe clinical effects on the CNS. Lead can increase spontaneous neurotransmitter release but decrease evoked neurotransmitter release. These effects may be caused by an interaction of lead with specific molecular targets involved in neurotransmitter release. We demonstrate here that the normally calcium-dependent binding characteristics of the synaptic vesicle protein synaptotagmin I are altered by lead. Nanomolar concentrations of lead induce the interaction of synaptotagmin I with phospholipid liposomes. The C2A domain of synaptotagmin I is required for lead-mediated phospholipid binding. Lead protects both recombinant and endogenous rat brain synaptotagmin I from proteolytic cleavage in a manner similar to calcium. However, lead is unable to promote the interaction of either recombinant or endogenous synaptotagmin I and syntaxin. Finally, nanomolar concentrations of lead are able to directly compete with and inhibit the ability of micromolar concentrations of calcium to induce the interaction of synaptotagmin I and syntaxin. Based on these findings, we conclude that synaptotagmin I may be an important, physiologically relevant target of lead.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Aspartic Acid
  • Binding Sites
  • Calcium-Binding Proteins / metabolism
  • Glutathione Transferase / metabolism
  • Lead / pharmacology*
  • Liposomes
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Phospholipids / metabolism
  • Qa-SNARE Proteins
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / metabolism
  • Synaptic Vesicles / metabolism*
  • Synaptotagmin I
  • Synaptotagmins
  • Terbium / pharmacokinetics


  • Calcium-Binding Proteins
  • Liposomes
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Phospholipids
  • Qa-SNARE Proteins
  • Recombinant Fusion Proteins
  • Synaptotagmin I
  • Syt1 protein, rat
  • Terbium
  • Synaptotagmins
  • Lead
  • Aspartic Acid
  • Glutathione Transferase